HNRNPD

Summary

HNRNPD (heterogeneous nuclear ribonucleoprotein D, HGNC:5036) is a protein-coding gene on chromosome 4q21.22, encoding Heterogeneous nuclear ribonucleoprotein D0 (Q14103). Binds with high affinity to RNA molecules that contain AU-rich elements (AREs) found within the 3’-UTR of many proto-oncogenes and cytokine mRNAs.

This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are nucleic acid binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two repeats of quasi-RRM domains that bind to RNAs. It localizes to both the nucleus and the cytoplasm. This protein is implicated in the regulation of mRNA stability. Alternative splicing of this gene results in four transcript variants.

Source: NCBI Gene 3184 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 58 total — 1 pathogenic, 3 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_031370

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5036
Approved symbol	HNRNPD
Name	heterogeneous nuclear ribonucleoprotein D
Location	4q21.22
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000138668
Ensembl biotype	protein_coding
OMIM	601324
Entrez	3184

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 48 protein_coding, 6 nonsense_mediated_decay, 1 retained_intron

ENST00000313899, ENST00000352301, ENST00000353341, ENST00000503822, ENST00000507010, ENST00000508119, ENST00000509107, ENST00000509263, ENST00000513584, ENST00000514325, ENST00000514671, ENST00000515432, ENST00000703968, ENST00000703969, ENST00000703970, ENST00000703971, ENST00000703972, ENST00000703973, ENST00000894839, ENST00000894840, ENST00000894841, ENST00000894842, ENST00000894843, ENST00000894844, ENST00000894845, ENST00000894846, ENST00000894847, ENST00000894848, ENST00000894849, ENST00000894850, ENST00000894851, ENST00000894852, ENST00000894853, ENST00000894854, ENST00000894855, ENST00000894856, ENST00000894857, ENST00000938591, ENST00000938592, ENST00000938593, ENST00000938594, ENST00000938595, ENST00000938596, ENST00000938597, ENST00000938598, ENST00000941924, ENST00000941925, ENST00000941926, ENST00000941927, ENST00000941928, ENST00000941929, ENST00000941930, ENST00000941931, ENST00000941932, ENST00000941933

RefSeq mRNA: 4 — MANE Select: NM_031370 NM_001003810, NM_002138, NM_031369, NM_031370

CCDS: CCDS3590, CCDS3591, CCDS3592, CCDS93554

Canonical transcript exons

ENST00000313899 — 9 exons

Exon	Start	End
ENSE00001181831	82371528	82371584
ENSE00001251846	82355304	82355401
ENSE00002072421	82352498	82354154
ENSE00003483277	82358659	82358820
ENSE00003499051	82356796	82356895
ENSE00003529851	82356537	82356683
ENSE00003604243	82373446	82373991
ENSE00003648751	82357313	82357444
ENSE00003654477	82359471	82359639

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 190.9855 / max 2274.0166, expressed in 1827 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52834	177.5113	1827
52836	3.7747	1430
52832	2.5685	1180
52833	2.3601	1060
203268	1.8015	945
52829	1.0915	605
52830	0.7651	452
52835	0.5825	312
52831	0.5301	280

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
embryo	UBERON:0000922	99.62	gold quality
ganglionic eminence	UBERON:0004023	99.62	gold quality
ventricular zone	UBERON:0003053	99.61	gold quality
epithelium of nasopharynx	UBERON:0001951	99.50	gold quality
cortical plate	UBERON:0005343	99.41	gold quality
tendon of biceps brachii	UBERON:0008188	99.37	gold quality
pylorus	UBERON:0001166	99.36	gold quality
endometrium	UBERON:0001295	99.35	gold quality
gingival epithelium	UBERON:0001949	99.29	gold quality
mammary duct	UBERON:0001765	99.26	gold quality
germinal epithelium of ovary	UBERON:0001304	99.24	gold quality
tonsil	UBERON:0002372	99.23	gold quality
epithelium of mammary gland	UBERON:0003244	99.22	gold quality
esophagus squamous epithelium	UBERON:0006920	99.22	gold quality
visceral pleura	UBERON:0002401	99.21	gold quality
parietal pleura	UBERON:0002400	99.20	gold quality
lymph node	UBERON:0000029	99.19	gold quality
pleura	UBERON:0000977	99.17	gold quality
colonic epithelium	UBERON:0000397	99.16	gold quality
left ovary	UBERON:0002119	99.14	gold quality
thymus	UBERON:0002370	99.14	gold quality
monocyte	CL:0000576	99.13	gold quality
vermiform appendix	UBERON:0001154	99.12	gold quality
caecum	UBERON:0001153	99.11	gold quality
ovary	UBERON:0000992	99.10	gold quality
superficial temporal artery	UBERON:0001614	99.10	gold quality
squamous epithelium	UBERON:0006914	99.10	gold quality
mononuclear cell	CL:0000842	99.09	gold quality
epithelium of esophagus	UBERON:0001976	99.09	gold quality
leukocyte	CL:0000738	99.08	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-13	yes	23.19
E-ANND-3	yes	11.00
E-CURD-88	yes	4.45
E-MTAB-8060	no	703.72
E-MTAB-6911	no	634.36
E-MTAB-3929	no	504.85
E-MTAB-7606	no	358.55
E-ENAD-20	no	327.69

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
KLF2	Unknown
TERT	Activation

Upstream regulators (CollecTRI, top): ATF5, E2F4, KHSRP, MEF2C, MYC, TP53

miRNA regulators (miRDB)

91 targeting HNRNPD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-10523-5P	99.91	69.22	2038

Literature-anchored findings (GeneRIF, showing 40)

• NMR structure of RNA binding domain and its interactions with RNA and DNA (PMID:11531333)
• bcl-2 A and U rich element-binding protein involved in bcl-2 mRNA destabilization during apoptosis. (PMID:11856759)
• regulates apoptosis by altering mRNA turnover and CDIR inhibits apoptosis by acting as a competitive inhibitor of AUF1, preventing AUF1 from binding to its targets (PMID:12356764)
• selective AUF1 phosphorylation may regulate ARE-directed mRNA turnover by remodeling local RNA structures (PMID:12819194)
• signal transduction pathways may regulate ARE-directed mRNA turnover by reversible phosphorylation of polysome-associated p40AUF1 (PMID:12819195)
• a mechanism whereby reduced cytoplasmic levels of AUF1 in MNT1 melanoma cells may lead to IL-10 overexpression, with deleterious consequences for tumor surveillance and rejection (PMID:14585195)
• composition and fate (stability, translation) of HuR- and/or AUF1-containing ribonucleoprotein complexes depend on the target mRNA of interest, RNA-binding protein abundance, stress condition, and subcellular compartment (PMID:15257295)
• calcineurin regulates AUF1 posttranslationally in vitro and PTH gene expression in vivo but still allows its physiological regulation by calcium and phosphate (PMID:15514034)
• analysis of the structure of the C-terminal-binding domain (BD2) of HNRPD complexed with single-stranded d(TTAGGG) determined by NMR (PMID:15734733)
• AUF1 binds to multiple destabilizing elements within the 3’-UTR that participate in the rapid turnover of the phosphoenolpyruvate carboxykinase mRNA. (PMID:15951444)
• coordinated regulation of mRNA stability by HuR and AUF1 proteins contributes to the observed increase in ATF3 expression following amino acid limitation (PMID:16109718)
• The multiple instability elements present within the 3’-UTR may function synergistically to mediate both the rapid degradation and the cAMP-induced stabilization of PEPCK mRNA. The latter process may result from a PKA-dependent phosphorylation of AUF1 (PMID:16144962)
• HuR shows increased binding to some V-ATPase mRNAs during ATP depletion; siRNA-mediated knockdown of HuR results in diminished V-ATPase expression. (PMID:16155006)
• c-Yes 3’-UTR contains at least three newly identified adenine/uridine-rich elements (AREs) which are bound specifically by ARE-binding proteins HuR and AUF1. (PMID:16289864)
• Differential expression of AU-rich mRNAs in response to LPL-mediated lipolysis might have an impact on physiological processes regulating lipid metabolism or pathophysiological processes promoting endothelial dysfunction and atherogenesis. (PMID:16494882)
• AUF1 could function in a novel pathway mediating the oncogenic effects of NPM-ALK (PMID:16835382)
• These results indicate that AUF1 binds to the AU-rich element in vivo and promotes IL-6 mRNA degradation. (PMID:16954375)
• AUF1 cell cycle variations define genomic DNA methylation by regulation of DNMT1 mRNA stability (PMID:17030625)
• Competitive binding of AUF1 and TIAR to MYC mRNA controls its translation. (PMID:17486099)
• Two mRNA binding proteins, HuR and AUF1, are colocalized and are capable of functional interaction in both the nucleus and cytoplasm. (PMID:17626845)
• both HuR and AUF1 bind to discrete regions of DENR/DRP mRNA and that AUF1 silencing increases DENR/DRP protein levels. (PMID:17878526)
• This study determined that hnRNP L interacts specifically with the hnRNP D/AUF1 in the yeast two-hybrid system. (PMID:18202450)
• Because AUF1 proteins are major components of messenger RNA stability complexes, our findings suggest that these complexes form a novel macromolecular target structure for autoantibodies in rheumatic autoimmune diseases (PMID:18240226)
• Chaperone Hsp27 is a novel subunit that is itself an AU-rich elements (ARE)-binding protein essential for rapid ARE-mRNA degradation. (PMID:18573886)
• UV cross-linking and immunoprecipitation experiments revealed 2 ARE-binding proteins, AUF1 and HuR, associated with IL-8 mRNA in saliva. (PMID:18650551)
• hnRNP D plays an important role in the translation of hepatitis C virus mRNA through interactions with the internal ribosomal entry site (PMID:18842733)
• isoform-specific regulation of anti-inflammatory IL10 expression in monocytes (PMID:18844578)
• Regulation of the hTERT promoter activity by MSH2, the hnRNPs K and D, and GRHL2 in human oral squamous cell carcinoma cells. (PMID:19015635)
• data demonstrate that AUF1 is an important factor that promotes iNOS mRNA degradation. Furthermore, all individual AUF1 isoforms act in a similar manner (PMID:19074427)
• AUF1 may be considered as a new, additional marker for thyroid carcinoma. (PMID:19574297)
• Immunofluorescent analysis revealed increased levels of HuR and AUF1, and a decrease in methyl-HuR levels in human livers with hepatocellular carcinoma. (PMID:20102719)
• Leukotriene B(4) BLT receptor signaling regulates the level and stability of cyclooxygenase-2 (COX-2) mRNA through restricted activation of Ras/Raf/ERK/p42 AUF1 pathway (PMID:20489206)
• the degradation of bcl-2 mRNA induced by AS1411 results from both interference with nucleolin protection of bcl-2 mRNA and recruitment of the exosome by AUF1. (PMID:20571027)
• Alternatively expressed domains of AU-rich element RNA-binding protein 1 (AUF1) regulate RNA-binding affinity, RNA-induced protein oligomerization, and the local conformation of bound RNA ligands (PMID:20926381)
• p40(AUF1) regulates a critical node within the NF-kappaB signaling pathway to permit IL10 induction for the anti-inflammatory arm of an innate immune response. (PMID:21135123)
• These results suggest that the p38 MAP kinase (MAPK)-MK2-Hsp27 signaling axis may target AUF1 destruction by proteasomes, thereby promoting AU-rich element mRNA stabilization. (PMID:21245386)
• Knockdown AUF1 mRNA expression by AUF1 siRNA in MKP-1 WT bone marrow macrophages significantly delayed degradation of IL-6, IL-10 and TNF- alpha mRNAs compared with controls (PMID:21733716)
• p16( INK4a) is also a modulator of transcription and apoptosis through controlling the expression of two major transcription regulators, AUF1 and E2F1 (PMID:21799732)
• This review briefly describes the roles of mRNA decay in gene expression in general and ARE-mediated decay (AMD) in particular, with a focus on AUF1 and the different modes of regulation that govern AUF1 involvement in AMD. (PMID:21956942)
• AUF1 and HuR bind to VEGFA ARE RNA under both normoxic and hypoxic conditions, and a pVHL-RNP complex determines VEGFA mRNA decay. (PMID:22086907)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hnrnpd	ENSDARG00000059246
mus_musculus	Hnrnpd	ENSMUSG00000000568
rattus_norvegicus	Hnrnpd	ENSRNOG00000002292

Paralogs (36): DAZAP1 (ENSG00000071626), CIRBP (ENSG00000099622), RBM23 (ENSG00000100461), RBM3 (ENSG00000102317), NCL (ENSG00000115053), TIA1 (ENSG00000116001), HNRNPA2B1 (ENSG00000122566), RBM19 (ENSG00000122965), RBM39 (ENSG00000131051), MSI1 (ENSG00000135097), HNRNPA1 (ENSG00000135486), HNRNPA1L2 (ENSG00000139675), RBMX (ENSG00000147274), A1CF (ENSG00000148584), TIAL1 (ENSG00000151923), RBM46 (ENSG00000151962), HNRNPDL (ENSG00000152795), MSI2 (ENSG00000153944), RBM47 (ENSG00000163694), RBMY1F (ENSG00000169800), HNRNPA3 (ENSG00000170144), RBMXL2 (ENSG00000170748), RBM4B (ENSG00000173914), RBM4 (ENSG00000173933), RBMXL3 (ENSG00000175718), HNRNPA0 (ENSG00000177733), TRNAU1AP (ENSG00000180098), HNRNPAB (ENSG00000197451), RBMXL1 (ENSG00000213516), HNRNPA1L3 (ENSG00000224578), RBMY1J (ENSG00000226941), RBMY1A1 (ENSG00000234414), RBMY1E (ENSG00000242389), RBMY1B (ENSG00000242875), RBMY1D (ENSG00000244395), DND1 (ENSG00000256453)

Protein

Protein identifiers

Heterogeneous nuclear ribonucleoprotein D0 — Q14103 (reviewed: Q14103)

Alternative names: AU-rich element RNA-binding protein 1

All UniProt accessions (12): Q14103, A0A994J440, A0A994J4B1, A0A994J4R1, A0A994J6S0, D6RAF8, D6RBP9, D6RBQ9, D6RD83, D6RF44, H0Y8G5, H0YA96

UniProt curated annotations — full annotation on UniProt →

Function. Binds with high affinity to RNA molecules that contain AU-rich elements (AREs) found within the 3’-UTR of many proto-oncogenes and cytokine mRNAs. Also binds to double- and single-stranded DNA sequences in a specific manner and functions a transcription factor. Each of the RNA-binding domains specifically can bind solely to a single-stranded non-monotonous 5’-UUAG-3’ sequence and also weaker to the single-stranded 5’-TTAGGG-3’ telomeric DNA repeat. Binds RNA oligonucleotides with 5’-UUAGGG-3’ repeats more tightly than the telomeric single-stranded DNA 5’-TTAGGG-3’ repeats. Binding of RRM1 to DNA inhibits the formation of DNA quadruplex structure which may play a role in telomere elongation. May be involved in translationally coupled mRNA turnover. Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain. May play a role in the regulation of the rhythmic expression of circadian clock core genes. Directly binds to the 3’UTR of CRY1 mRNA and induces CRY1 rhythmic translation. May also be involved in the regulation of PER2 translation.

Subunit / interactions. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Part of a complex associated with the FOS mCRD domain and consisting of PABPC1, PAIP1, CSDE1/UNR and SYNCRIP. Interacts with IGF2BP2. Interacts with GTPBP1. Interacts with EIF4G1; the interaction requires RNA. Interacts with EIF3B and RPS3.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Arg-345 is dimethylated, probably to asymmetric dimethylarginine. Methylated by PRMT1, in an insulin-dependent manner. The PRMT1-mediated methylation regulates tyrosine phosphorylation.

Isoforms (4)

UniProt ID	Names	Canonical?
Q14103-1	1, p45, Dx9	yes
Q14103-2	2, p42, Dx4
Q14103-3	3, p40, Dx7
Q14103-4	4, p37

RefSeq proteins (4): NP_001003810, NP_002129, NP_112737, NP_112738* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR012956	CARG-binding_factor_N	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF00076, PF08143

UniProt features (63 total): modified residue 25, strand 14, helix 6, compositionally biased region 4, cross-link 3, domain 2, splice variant 2, sequence conflict 2, turn 2, initiator methionine 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5IM0	X-RAY DIFFRACTION	1.7
2Z5N	X-RAY DIFFRACTION	3.2
1HD0	SOLUTION NMR
1HD1	SOLUTION NMR
1IQT	SOLUTION NMR
1WTB	SOLUTION NMR
1X0F	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14103-F1	63.80	0.12

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (28): 71, 80, 82, 83, 91, 119, 127, 165, 190, 193, 243, 251, 271, 272, 278, 280, 282, 345, 345, 345 …

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-450408	AUF1 (hnRNP D0) binds and destabilizes mRNA
R-HSA-9918487	Dengue Virus Genome Translation and Replication

MSigDB gene sets: 430 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, MORF_DNMT1, GOBP_HINDBRAIN_DEVELOPMENT, E2F_Q4_01, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, MORF_ESPL1, GOBP_POSITIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS

GO Biological Process (33): liver development (GO:0001889), regulation of DNA-templated transcription (GO:0006355), RNA processing (GO:0006396), RNA catabolic process (GO:0006401), regulation of gene expression (GO:0010468), cerebellum development (GO:0021549), positive regulation of telomere maintenance via telomerase (GO:0032212), regulation of circadian rhythm (GO:0042752), positive regulation of translation (GO:0045727), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), response to calcium ion (GO:0051592), response to electrical stimulus (GO:0051602), 3’-UTR-mediated mRNA destabilization (GO:0061158), CRD-mediated mRNA stabilization (GO:0070934), cellular response to amino acid stimulus (GO:0071230), cellular response to estradiol stimulus (GO:0071392), cellular response to nitric oxide (GO:0071732), circadian regulation of translation (GO:0097167), negative regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:1900152), response to rapamycin (GO:1901355), positive regulation of telomere capping (GO:1904355), response to sodium phosphate (GO:1904383), cellular response to putrescine (GO:1904586), hepatocyte dedifferentiation (GO:1990828), positive regulation of cytoplasmic translation (GO:2000767), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), response to estradiol (GO:0032355), regulation of mRNA stability (GO:0043488), rhythmic process (GO:0048511), regulation of RNA metabolic process (GO:0051252)

GO Molecular Function (10): minor groove of adenine-thymine-rich DNA binding (GO:0003680), chromatin binding (GO:0003682), RNA binding (GO:0003723), mRNA 3’-UTR AU-rich region binding (GO:0035925), telomeric repeat DNA binding (GO:0042162), histone deacetylase binding (GO:0042826), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), mRNA binding (GO:0003729), protein binding (GO:0005515)

GO Cellular Component (10): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), postsynaptic density (GO:0014069), glutamatergic synapse (GO:0098978), mCRD-mediated mRNA stability complex (GO:0106002), ribonucleoprotein complex (GO:1990904), cytoplasm (GO:0005737), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Dengue Virus Infection	2
mRNA Splicing	1
Metabolism of RNA	1
mRNA 3’-end processing	1
Regulation of mRNA stability by proteins that bind AU-rich elements	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	3
DNA-templated transcription	2
gene expression	2
circadian rhythm	2
regulation of translation	2
cellular response to oxygen-containing compound	2
nucleic acid binding	2
protein-containing complex	2
gland development	1
hepaticobiliary system development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
RNA biosynthetic process	1
primary metabolic process	1
RNA metabolic process	1
nucleic acid catabolic process	1
regulation of macromolecule biosynthetic process	1
metencephalon development	1
anatomical structure development	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomerase	1
positive regulation of telomere maintenance via telomere lengthening	1
positive regulation of DNA biosynthetic process	1
regulation of biological process	1
translation	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
response to metal ion	1
response to abiotic stimulus	1
mRNA destabilization	1
mRNA stabilization	1
response to amino acid	1
cellular response to acid chemical	1
response to estradiol	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

273 interactions, top by confidence:

A	B	Type	Score
HNRNPC	KPNA3	psi-mi:“MI:0914”(association)	0.850
IFIT2	IFIT3	psi-mi:“MI:0914”(association)	0.780
HNRNPU	HNRNPD	psi-mi:“MI:0915”(physical association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HNRNPD	HNRNPA2B1	psi-mi:“MI:0915”(physical association)	0.670
USE1	NBAS	psi-mi:“MI:0914”(association)	0.640
IGF2BP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
HNRNPDL	HNRNPD	psi-mi:“MI:0915”(physical association)	0.560
HNRNPD	HNRNPDL	psi-mi:“MI:0914”(association)	0.560
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
HNRNPD	LDHAL6B	psi-mi:“MI:0915”(physical association)	0.520
LDHAL6B	HNRNPD	psi-mi:“MI:0915”(physical association)	0.520
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
RBM45	HNRNPDL	psi-mi:“MI:0914”(association)	0.460
AURKA	CCNB2	psi-mi:“MI:0915”(physical association)	0.400
ATRX	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
MAPT	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
JAK1	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
C2CD6	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
NCOA3	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
ANKRD12	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
HEBP2	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
ANKRD20A12P	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
RAP1A	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (991): HNRNPD (Affinity Capture-Western), NCL (Affinity Capture-Western), KAT2B (Affinity Capture-Western), KAT2B (Co-localization), HNRNPD (Affinity Capture-MS), HNRNPD (Affinity Capture-Western), ING4 (Affinity Capture-Western), HNRNPD (Reconstituted Complex), MYC (Protein-RNA), HNRNPD (Affinity Capture-RNA), HNRNPD (Affinity Capture-RNA), HNRNPD (Affinity Capture-RNA), HNRNPD (Affinity Capture-RNA), HNRNPD (Affinity Capture-MS), HNRNPD (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8Y4L2, A5A6H4, A7VJC2, O88569, O89086, P04256, P07909, P09651, P09867, P17130, P21522, P22626, P48810, P49312, P51968, P51989, P51990, P51991, P51992, P60824, P60825, P60826, P98179, Q13151, Q14011, Q14103, Q22037, Q24491, Q28521, Q28IQ9, Q2HJ60, Q32P51, Q3SWU3, Q5RBU8, Q5RF83, Q5ZI72, Q640A2, Q6NU14, Q6URK4, Q7ZX83

Diamond homologs: A0A0A0LLY1, A0A0D1C8Z4, A5A6M3, C0HFE5, D3Z4I3, D4AE41, M0R7T6, O22703, O35698, O75526, O89086, O93235, P04147, P0C8Z4, P10979, P19682, P19683, P19684, P28644, P38159, P39697, P48809, P49310, P49311, P49313, P49314, P60824, P60825, P60826, P84586, P98179, Q03250, Q03251, Q03878, Q04836, Q05966, Q08473, Q08935, Q08937, Q14011

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GSK3B	“down-regulates activity”	HNRNPD	phosphorylation
GSK3B	down-regulates	HNRNPD	phosphorylation
PRKACA	up-regulates	HNRNPD	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 172 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Processing of Capped Intron-Containing Pre-mRNA	18	11.5×	1e-11
DNA Damage Recognition in GG-NER	5	11.1×	6e-03
mRNA Polyadenylation	16	10.9×	4e-10
mRNA Splicing	9	7.7×	4e-04
mRNA Splicing - Major Pathway	18	7.6×	5e-09
Dengue Virus-Host Interactions	16	5.7×	4e-06
Neddylation	13	4.8×	4e-04
Metabolism of RNA	13	4.2×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cytoplasmic translation	6	39.6×	2e-06
alternative mRNA splicing, via spliceosome	5	22.5×	4e-04
mRNA stabilization	6	14.7×	4e-04
intrinsic apoptotic signaling pathway	6	14.3×	4e-04
mRNA transport	7	12.3×	3e-04
mRNA splicing, via spliceosome	20	12.2×	3e-13
autophagosome maturation	5	11.7×	4e-03
mitophagy	5	10.6×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

58 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	3
Uncertain significance	36
Likely benign	2
Benign	8

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
3026803	NM_031370.3(HNRNPD):c.104_105del (p.Gln35fs)	Pathogenic
3376744	NM_031370.3(HNRNPD):c.802C>T (p.Gln268Ter)	Likely pathogenic
3897622	NM_031370.3(HNRNPD):c.257_258dup (p.Ser87fs)	Likely pathogenic
3897642	NM_031370.3(HNRNPD):c.796C>T (p.Gln266Ter)	Likely pathogenic

SpliceAI

1415 predictions. Top by Δscore:

Variant	Effect	Δscore
4:82354151:CCAC:C	acceptor_gain	1.0000
4:82354152:CAC:C	acceptor_gain	1.0000
4:82354152:CACC:C	acceptor_gain	1.0000
4:82354929:AC:A	donor_gain	1.0000
4:82354930:CC:C	donor_gain	1.0000
4:82355402:C:CC	acceptor_gain	1.0000
4:82356531:A:AC	donor_gain	1.0000
4:82356532:C:CC	donor_gain	1.0000
4:82356532:CTTA:C	donor_gain	1.0000
4:82356534:TAC:T	donor_loss	1.0000
4:82356535:A:AC	donor_gain	1.0000
4:82356535:A:T	donor_loss	1.0000
4:82356535:ACTG:A	donor_gain	1.0000
4:82356536:C:CA	donor_gain	1.0000
4:82356536:C:G	donor_loss	1.0000
4:82356536:CT:C	donor_gain	1.0000
4:82356536:CTG:C	donor_gain	1.0000
4:82356536:CTGC:C	donor_gain	1.0000
4:82356536:CTGCT:C	donor_gain	1.0000
4:82356684:C:CC	acceptor_gain	1.0000
4:82356783:G:C	donor_gain	1.0000
4:82356791:CTTA:C	donor_loss	1.0000
4:82356792:TTA:T	donor_loss	1.0000
4:82356793:TAC:T	donor_loss	1.0000
4:82356794:A:AC	donor_gain	1.0000
4:82356794:A:T	donor_loss	1.0000
4:82356795:C:CC	donor_gain	1.0000
4:82356818:T:TA	donor_gain	1.0000
4:82356891:TCACA:T	acceptor_gain	1.0000
4:82356892:CACA:C	acceptor_gain	1.0000

AlphaMissense

2336 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:82356879:G:T	A257D	1.000
4:82356884:T:A	K255N	1.000
4:82356884:T:G	K255N	1.000
4:82356885:T:A	K255I	1.000
4:82356886:T:C	K255E	1.000
4:82356888:A:C	I254R	1.000
4:82356888:A:T	I254K	1.000
4:82356891:T:A	E253V	1.000
4:82356892:C:T	E253K	1.000
4:82356893:A:C	C252W	1.000
4:82356894:C:A	C252F	1.000
4:82356894:C:T	C252Y	1.000
4:82356895:A:G	C252R	1.000
4:82357326:A:T	V247D	1.000
4:82357333:G:C	H245D	1.000
4:82357350:A:T	I239K	1.000
4:82357376:A:C	F230L	1.000
4:82357376:A:T	F230L	1.000
4:82357377:A:G	F230S	1.000
4:82357378:A:G	F230L	1.000
4:82357383:A:C	I228S	1.000
4:82357383:A:T	I228N	1.000
4:82357385:A:C	F227L	1.000
4:82357385:A:T	F227L	1.000
4:82357386:A:C	F227C	1.000
4:82357386:A:G	F227S	1.000
4:82357387:A:C	F227V	1.000
4:82357387:A:G	F227L	1.000
4:82357387:A:T	F227I	1.000
4:82357388:G:C	C226W	1.000

dbSNP variants (sampled 300 via entrez): RS1000020840 (4:82372187 G>A), RS1000140846 (4:82373033 A>G), RS1000264328 (4:82373634 T>TGCC), RS10003180 (4:82367272 T>G), RS1000346487 (4:82363694 T>A), RS1000388298 (4:82362078 T>C,G), RS1000435610 (4:82368971 T>C), RS1000462072 (4:82362422 T>G), RS1000468359 (4:82369158 G>A), RS1000475734 (4:82373750 T>A), RS1000590837 (4:82368351 C>A), RS1000657452 (4:82366962 C>G,T), RS1000798685 (4:82363595 G>A), RS1000803544 (4:82368021 C>T), RS1001000647 (4:82372873 G>A)

Disease associations

OMIM: gene MIM:601324 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant
neurodevelopmental disorder	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (3): neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST007565_16	Morning person	3.000000e-14
GCST007576_46	Chronotype	3.000000e-14
GCST010002_9	Refractive error	2.000000e-65
GCST010479_68	Coronary artery disease	4.000000e-08
GCST010866_22	Coronary artery disease	2.000000e-13
GCST90013406_149	Liver enzyme levels (alkaline phosphatase)	3.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296009 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.57	Kd	26.66	nM	CHEMBL5653589
7.57	ED50	26.66	nM	CHEMBL5653589
5.94	Kd	1149	nM	CHEMBL3752910
5.94	ED50	1149	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148529: Binding affinity to human HNRNPD incubated for 45 mins by Kinobead based pull down assay	kd	0.0267	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148529: Binding affinity to human HNRNPD incubated for 45 mins by Kinobead based pull down assay	kd	1.1493	uM

CTD chemical–gene interactions

89 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, affects cotreatment, increases expression, decreases expression, increases abundance	5
Benzo(a)pyrene	decreases expression, increases expression	5
bisphenol A	affects expression, affects splicing, decreases expression	4
Valproic Acid	affects expression, decreases expression	4
cobaltous chloride	affects cotreatment, decreases expression, increases expression	3
Acetaminophen	affects expression, decreases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Cisplatin	affects reaction, decreases expression	2
Doxorubicin	decreases response to substance, affects phosphorylation, affects response to substance	2
Formaldehyde	decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Quercetin	affects phosphorylation, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	increases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
methylparaben	affects splicing, decreases expression, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
butylidenephthalide	increases expression	1
lead chloride	affects cotreatment, decreases expression	1
coumarin	increases phosphorylation	1
cadmium sulfate	affects cotreatment, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119042	Binding	Binding affinity to HNRNPD in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2V5	SEES3-1V human HNRNPD, clone1	Embryonic stem cell	Male
CVCL_A2V6	SEES3-1V human HNRNPD, clone2	Embryonic stem cell	Male
CVCL_A2V7	SEES3-1V human HNRNPD, clone3	Embryonic stem cell	Male
CVCL_B0Z0	Abcam U2OS HNRNPD KO	Cancer cell line	Female
CVCL_C0RH	HeLa HNRNPD-/- cl10	Cancer cell line	Female
CVCL_C0RI	HeLa HNRNPD-/- cl4	Cancer cell line	Female

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development